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Role of class II human leucocyte antigens in the progression from early to definite systemic sclerosis
Barbara Vigone1, Alessandro Santaniello1, Maurizio Marchini1
1Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Insights
Certain HLA class II alleles, specifically the HLA DQ5-DR1 haplotype, are linked to slower disease progression in patients with early systemic sclerosis (SSc). This genetic factor appears independent of anti-centromere antibody (ACA) status, suggesting a protective role in SSc advancement.
Area of Science:
- Immunogenetics
- Rheumatology
- Systemic Sclerosis Pathogenesis
Background:
- Human Leukocyte Antigen (HLA) associations with systemic sclerosis (SSc) susceptibility are well-established, yet their influence on disease progression remains unclear.
- The 2013 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria facilitate early identification of SSc patients.
- Understanding genetic factors influencing the transition from early to definite SSc is crucial for predicting disease course.
Purpose of the Study:
- To investigate the role of HLA class II antigens in the progression of SSc from early to definite stages.
- To identify specific HLA alleles or haplotypes associated with SSc disease progression rates.
- To evaluate the independent and combined effects of genetic factors and clinical markers on SSc progression.
Main Methods:
- A cohort of 158 subjects with early SSc, meeting LeRoy and Medsger criteria without definite SSc manifestations at referral, was analyzed.
- High-resolution HLA class II typing was performed for all participants.
- Progression to definite SSc was assessed retrospectively, with survival analysis used to evaluate the impact of genetic and clinical variables.
Main Results:
- The median time to SSc progression was 45 months, with 5-year and 10-year progression rates of 59.8% and 80%, respectively.
- Anti-centromere antibodies (ACAs) were associated with a reduced risk of progression (median survival 55 vs. 23 months).
- Carriers of the HLA DQ5-DR1 haplotype (HLA-DRB1*0101-HLA-DQA1*0101(4)-HLA-DQB1*0501) exhibited significantly lower progression rates (median survival 108 vs. 44 months), an effect independent of ACA status.
Conclusions:
- Specific HLA class II alleles within the HLA DQ5-DR1 haplotype are associated with a slower rate of progression from early to definite systemic sclerosis.
- The HLA DQ5-DR1 haplotype demonstrates a protective effect against SSc disease advancement.
- Genetic predisposition, as indicated by HLA type, plays a significant role in SSc progression, independent of common clinical markers like ACA positivity.
Objective:
HLAs have been extensively associated with SSc susceptibility but their role in the progression of the disease is poorly understood. In 2013 the ACR and European League Against Rheumatism (EULAR) jointly defined criteria for the classification of SSc that allow the early identification of definite SSc patients. In this study we investigated the role of HLA class II antigens in the progression from early to definite SSc.
Methods:
One hundred and fifty-eight subjects with early SSc according to LeRoy and Medsger criteria and no other manifestation indicative of definite SSc at referral were considered. All the patients underwent high-resolution HLA class II typing and the appraisal of definite SSc was retrospectively conducted in a prospective manner. Lifetime analysis was conducted to gauge the effect of genetic and clinical characteristics on progression of the disease.
Results:
The median estimated time to progression was 45 months from referral; the 5 and 10 year estimates of progression were 59.8% and 80%, respectively. ACAs were associated with a reduced risk of progression [median survival 55 vs 23 months for ACA-positive vs ACA-negative patients, P = 0.035; hazard ratio (HR) 0.67 (95% CI 0.458, 0.979)]. HLA alleles within the HLA DQ5-DR1 haplotype [HLA-DRB1*0101-HLA-DQA1*0101(4)-HLA-DQB1*0501] reduced the risk of progression of the disease [median survival 108 vs 44 months for DQ5-DR1 carriers vs DQ5-DR1 non-carriers; HR 0.388 (CI 0.211, 0.712), P = 0.001, corrected P = 0.014]. In multivariate models, the effect of genetics was found to be independent of ACA positivity or other baseline factors; additive risks were observed when the DQ5-DR1 haplotype and ACA were jointly considered.
Conclusion:
HLA class II alleles within the HLA DQ5-DR1 haplotype are associated with lower rates of progression from early to definite SSc.
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